Phosphate tightly associated with protein has been known since the late nineteenth century. Since then, a variety of covalent linkages of phosphate to proteins have been found. The most common involve esterification of phosphate to serine and threonine, with smaller amounts being covalently linked to lysine, arginine, histidine, aspartic acid, glutamic acid, and cysteine. The occurrence of phosphorylated proteins implies the existence of one or more protein kinases capable of phosphorylating amino acid residues on proteins, and also of protein phosphatases capable of hydrolyzing phosphorylated amino acid residues on proteins.
Protein kinases play critical roles in the regulation of biochemical and morphological changes associated with cellular growth and division (D""Urso, G. et al. (1990) Science 250: 786-791; Birchmeier. C. et al. (1993) Bioessays 15: 185-189). They serve as growth factor receptors and signal transducers and have been implicated in cellular transformation and malignancy (Hunter, T. et al. (1992) Cell 70: 375-387; Posada, J. et al. (1992) Mol. Biol. Cell 3: 583-592; Hunter, T. et al. (1994) Cell 79: 573-582). For example, protein kinases have been shown to participate in the transmission of signals from growth-factor receptors (Sturgill, T. W. et al. (1988) Nature 344: 715-718; Gomez, N. et al. (1991) Nature 353: 170-173), control of entry of cells into mitosis (Nurse, P. (1990) Nature 344: 503-508; Maller, J. L. (1991) Curr. Opin. Cell Biol. 3: 269-275) and regulation of actin bundling (Husain-Chishti, A. et al. (1988) Nature 334: 718-721).
The overall level, in cells, of protein tyrosine phosphorylation, as well as the phosphorylated state of any given protein, arises from the balance of Protein Tyrosine Kinase (PTK) and Protein Tyrosine Phosphatase (PTPase) activities. Thus PTPases have been proposed as key regulatory elements of cell growth control (Hunter, 1989, Cell 58:1013-1016).
PTKs were discovered and characterized more than one decade earlier than PTPases and in the last few years a large number of studies has led to the identification of many new PTPases and some of them have been accurately characterized. In addition, findings on the biological role of some PTPases in cells have recently been reported (Pondaven, 1991, Adv Prot Phosphatases 6:35-57). Current work suggests that PTKs and PTPases are equally important in many biological processes ranging from cell growth control to cell differentiation and development. In particular, the ocogenic potential of PTKs and the ability of PTPases to counteract PTK oncogenic activation by antiproliferative action suggests that the genes coding for PTPases, in many instances, may be considered tumor-suppressing genes or even anti-oncogenes
The existence of PTPases was first predicted to explain the rapid loss of phosphorylation of in vitro phosphorylated membrane proteins (Carpenter et al., 1979, J Biol Chem 254:4884-4891). The main PTPase in human placenta (PTP1B) was purified to homogeneity and sequenced (Tonks et al., 1988, J Biol Chem 263:6722-2730;
Charbonneau et al., 1989, PNAS USA 86:5252-5256). Sequence homology between the catalytic domain of PTP1B and the leukocyte common antigen (LCA, or CD45) was demonstrated, indicating that PTPases can be considered a family of structurally related molecules.
The effects of many growth factors such as NGF, BDNF, NT3, FGF, insulin and IGF1 are known to be mediated by high-affinity receptors with tyrosine kinases activity (Fantl et al. Annu. Rev. Biochem., 62 (1993) 453-481; Schlessinger and Ulrich Neuron, 9 (1992) 383-391; Ullrich and Schlessinger Cell, 61 (1990) 203-212). Expression of several tyrosine phosphatase genes has been detected in the brain (Jones et al. J. Biol. Chem., 264 (1989) 7747-7753), including RPTPxcex1(Kaplan et al. Proc. Natl. Acad. Sci. USA, 87 91990) 7000-7004; Sap et al. Proc. Natl. Acad. Sci. USA, 87 (1990) 6112-6116), RNPTPX (Guan et al. Proc. Natl. Acad. Sci. USA, 87 (19910) 1501-1505), STEP (Lombroso et al. Proc. Natl. Acad. Sci. USA, 88 (1991) 7242-7246), SH-PTP2 (Freeman et al. Proc. Natl. Acad. Sci. USA, 89 (1992) 11239-11243), MPTPxcex4 (Mizuno et al. Mol. Cell. Biol., 13 (1993) 5513-5523), DPTP99A and DPTP10D (Yang et al. Cell, 67 (1991) 661-673).
Intraventricular administration of either NGF, BDNF, insulin or IGF1 prevents delayed neuronal death in the CA1 subfield of the hippocampus (Beck et al. J. Cereb Blood Flow Metab., 14 (1994) 689-692; Shigeno et al. J. Neurosci., 11 (1991) 2914-2919; Zhu and Auer J. Cereb. Blood Flow Metab., 14 (1994) 237-242).
Tyrosine kinase inhibitors block the tyrosine phosphorylation of MAP kinase (Blenis Proc. Natl. Acad. Sci. USA, 90 (1993) 5889-5892; Pelech and Sanghera Science, 257 (1992) 1335-1356) and prevent delayed neuronal death after forebrain ischemia (Kindy J. Cereb. Blood Flow Metab, 13 (1993) 372-377). During reperfusion after ischemia, tyrosine phosphorylation of proteins increases in the hippocampus but some proteins in the hippocampus are dephosphorylated (Campos-Gonzalez J. Neurochem., 59 (1992) 1955-1958; Hu and Wieloch J. Neurochem, 62 (1994) 1357-1367; Takano et al. J. Cereb. Blood Flow Metab., 15 (1995) 33-41). These observations suggest that tyrosine phosphorylation plays an important role in the delayed neuronal death which occurs as a result of ischemia-reperfusion injury.
A number of PTPases, in addition to the hydrolytic activity on phosphotyrosine, show some phosphoserine/phosphothreonine phosphatase activity. These enzymes, mostly localized in the nucleus and referred to as dual-specificity PTPases (dsPTPases), are emerging as a subclass of PTPases acting as important regulators of cell cycle control and mitogenic signal transduction possibly by controlling the activity of signal transduction proteins like ERK. In fact, they appear responsible for in vivo nuclear dephosphorylation and inactivation of nuclear dephosphorylation and inactivation of MAP kinases (Alessi et al., 1995, Curr Biol 5:195-283). These enzymes exhibit sequence identity to the vaccinia H-1 gene product, the first identified dsPTPase (Guan et al., 1991, Nature 350:359-362). Several dsPTPases differing from each other in length have been identified. These enzymes and the other PTPase subclasses share an active site sequence motif showing only a limited sequence homology beyond this region.
Given the importance of such protein tyrosine phosphatases in the regulation of the cell cycle, there exists a need to identify novel protein tyrosine phosphatases which function as modulators in the cell cycle such as the suppression of proliferation and whose aberrant function can result in disorders arising from improper cell cycle regulation such as cancer.
The present invention is based, at least in part, on the discovery of novel nucleic acid molecules and proteins encoded by such nucleic acid molecules, referred herein as xe2x80x9cCardiovascular System Associated Protein Tyrosine Phosphatasexe2x80x9d (xe2x80x9cCSAPTPxe2x80x9d) proteins. The CSAPTP nucleic acid and protein molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes, e.g., cardiac cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding CSAPTP proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of CSAPTP-encoding nucleic acids.
In one embodiment, a CSAPTP nucleic acid molecule of the invention is at least 57% or more homologous to a nucleotide sequence (e.g., to the entire length of the nucleotide sequence) including SEQ ID NO:1, SEQ ID NO:3, or a complement thereof. In another embodiment, a CSAPTP nucleic acid molecule is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more homologous to a nucleotide sequence including SEQ ID NO:4, SEQ ID NO:6, or a complement thereof. In yet another embodiment, a CSAPTP nucleic acid molecule is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more homologous to a nucleotide sequence including SEQ ID NO:7, SEQ ID NO:9, or a complement thereof.
In a preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown SEQ ID NO:1or 3, or a complement thereof. In another embodiment, the nucleic acid molecule includes SEQ ID NO:3 and nucleotides 1-248 of SEQ ID NO:1. In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:1 or 3. In another preferred embodiment, the nucleic acid molecule comprises a fragment of at least 499 nucleotides of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, or a complement thereof.
In another preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown SEQ ID NO:4 or 6, or a complement thereof. In another embodiment, the nucleic acid molecule includes SEQ ID NO:6 and nucleotides 1-342 of SEQ ID NO:4. In another embodiment, the nucleic acid molecule includes SEQ ID NO:6 and nucleotides 790-1016 of SEQ ID NO:4. In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:4 or 6. In another preferred embodiment, the nucleic acid molecule comprises a fragment of at least 626 nucleotides of the nucleotide sequence of SEQ ID NO:4, SEQ ID NO:6, or a complement thereof.
In another preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown SEQ ID NO:7 or 9, or a complement thereof. In another embodiment, the nucleic acid molecule includes SEQ ID NO:9 and nucleotides 628-814 of SEQ ID NO:7. In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:7 or 9. In another preferred embodiment, the nucleic acid molecule comprises a fragment of at least 531 nucleotides of the nucleotide sequence of SEQ ID NO:7, SEQ ID NO:9, or a complement thereof.
In another embodiment, a CSAPTP nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8. In a preferred embodiment, a CSAPTP nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 79%, 80%, 85%, 90%, 95%, 99% or more homologous to an amino acid sequence including SEQ ID NO:2 (e.g., the entire amino acid sequence of SEQ ID NO:2). In another preferred embodiment, a CSAPTP nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 10%, 15%, 20%, 23%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more homologous to an amino acid sequence including SEQ ID NO:5 (e.g., the entire amino acid sequence of SEQ ID NO:5). In yet another preferred embodiment, a CSAPTP nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 10%, 15%, 20%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more homologous to an amino acid sequence including SEQ ID NO:8 (e.g., the entire amino acid sequence of SEQ ID NO:8).
In another preferred embodiment, an isolated nucleic acid molecule encodes the amino acid sequence of a human CSAPTP. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein which includes the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8.
Another embodiment of the invention features nucleic acid molecules, preferably CSAPTP nucleic acid molecules, which specifically detect CSAPTP nucleic acid molecules relative to nucleic acid molecules encoding non-CSAPTP proteins. For example, in one embodiment, such a nucleic acid molecule is at least 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7, or a complement thereof. In a particularly preferred embodiment, the nucleic acid molecule comprises a fragment of at least 994 nucleotides of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, or a complement thereof. In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 1-17 and 1011-1315 of SEQ ID NO:1.
In another particularly preferred embodiment, the nucleic acid molecule comprises a fragment of at least 626 nucleotides of the nucleotide sequence of SEQ ID NO:4, SEQ ID NO:6, or a complement thereof. In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 1-342 of SEQ ID NO:4. In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 1002-1016 of SEQ ID NO:4.
In another particularly preferred embodiment, the nucleic acid molecule comprises a fragment of at least 531 nucleotides of the nucleotide sequence of SEQ ID NO:7, SEQ ID NO:9, or a complement thereof. In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 1-103 and 774-814 of SEQ ID NO:7.
In other preferred embodiments, the nucleic acid molecule encodes a naturally occurring allelic variant of a polypeptide which includes the amino acid sequence of SEQ ID NO:2, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule which includes SEQ ID NO:1or SEQ ID NO:3 under stringent conditions. In other preferred embodiments, the nucleic acid molecule encodes a naturally occurring allelic variant of a polypeptide which includes the amino acid sequence of SEQ ID NO:5, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule which includes SEQ ID NO:4 or SEQ ID NO:6 under stringent conditions. In other preferred embodiments, the nucleic acid molecule encodes a naturally occurring allelic variant of a polypeptide which includes the amino acid sequence of SEQ ID NO:8, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule which includes SEQ ID NO:7 or SEQ ID NO:9 under stringent conditions.
Another embodiment of the invention provides an isolated nucleic acid molecule which is antisense to a CSAPTP nucleic acid molecule, e.g., the coding strand of a CSAPTP nucleic acid molecule.
Another aspect of the invention provides a vector comprising a CSAPTP nucleic acid molecule. In certain embodiments, the vector is a recombinant expression vector. In another embodiment, the invention provides a host cell containing a vector of the invention. The invention also provides a method for producing a protein, preferably a CSAPTP protein, by culturing in a suitable medium, a host cell, e.g., a mammalian host cell such as a non-human mammalian cell, of the invention containing a recombinant expression vector, such that the protein is produced.
Another aspect of this invention features isolated or recombinant CSAPTP proteins and polypeptides. In one embodiment, the isolated protein, preferably a CSAPTP-1 protein, includes at least one CSAPTP-1 unique N-terminal domain and at least one phosphatase active domain. In another embodiment, the isolated protein, preferably a CSAPTP-1 protein, includes at least one CSAPTP-1 unique N-terminal domain and at least one phosphatase active domain and has an amino acid sequence which is at least 50%, 55%, 60%, 65%, 70%, 75%, 79%, 80%, 85%, 90%, 95%, 99% or more homologous to a amino acid sequence including SEQ ID NO:2. In yet another embodiment, the isolated protein, preferably a CSAPTP-1 protein, includes at least one CSAPTP-1 unique N-terminal domain and at least one phosphatase active domain and is expressed and/or functions in cells of the cardiovascular system. In an even further embodiment, the isolated protein, preferably a CSAPTP-1 protein, includes at least one CSAPTP-1 unique N-terminal domain and at least one phosphatase active domain and plays a role in signalling pathways associated with cellular growth, e.g., signalling pathways associated with cell cycle regulation. In another embodiment, the isolated protein, preferably a CSAPTP-1 protein, includes at least one CSAPTP unique N-terminal domain and at least one phosphatase active domain and is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3.
In another embodiment, the isolated protein, preferably a CSAPTP-2 protein, includes at least one CSAPTP-2 unique N-terminal domain and at least one phosphatase active domain. In another embodiment, the isolated protein, preferably a CSAPTP-2 protein, includes at least one CSAPTP-2 unique N-terminal domain and at least one phosphatase active domain and has an amino acid sequence which is at least 10%, 15%, 20%, 23%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, 99% or more homologous to an amino acid sequence including SEQ ID NO:5.
In yet another embodiment, the isolated protein, preferably a CSAPTP-2 protein, includes at least one CSAPTP-2 unique N-terminal domain and at least one phosphatase active domain and is expressed and/or functions in cells of the cardiovascular system. In an even further embodiment, the isolated protein, preferably a CSAPTP-2 protein, includes at least one CSAPTP-2 unique N-terminal domain and at least one phosphatase active domain and plays a role in signalling pathways associated with cellular growth, e.g., signalling pathways associated with cell cycle regulation. In another embodiment, the isolated protein, preferably a CSAPTP-2 protein, includes at least one CSAPTP-2 unique N-terminal domain and at least one phosphatase active domain and is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:4 or SEQ ID NO:6.
In yet another embodiment, the isolated protein, preferably a CSAPTP-3 protein, includes at least one CSAPTP-3 unique N-terminal domain and at least one phosphatase active domain. In another embodiment, the isolated protein, preferably a CSAPTP-3 protein, includes at least one CSAPTP-3 unique N-terminal domain and at least one phosphatase active domain and has an amino acid sequence which is at least 10%, 15%, 20%,24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more homologous to an amino acid sequence including SEQ ID NO:8.
In yet another embodiment, the isolated protein, preferably a CSAPTP-3 protein, includes at least one CSAPTP-3 unique N-terminal domain and at least one phosphatase active domain and is expressed and/or functions in cells of the cardiovascular system. In an even further embodiment, the isolated protein, preferably a CSAPTP-3 protein, includes at least one CSAPTP-3 unique N-terminal domain and at least one phosphatase active domain and plays a role in signalling pathways associated with cellular growth, e.g., signalling pathways associated with cell cycle regulation. In another embodiment, the isolated protein, preferably a CSAPTP-3 protein, includes at least one CSAPTP-3 unique N-terminal domain and at least one phosphatase active domain and is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:7 or SEQ ID NO:9.
In another embodiment, the isolated protein, preferably a CSAPTP protein, has an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8. In a preferred embodiment, the protein, preferably a CSAPTP protein, has an amino acid sequence at least 79%, 23%, 24% or more homologous to an amino acid sequence including SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8, respectively (e.g., the entire amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8). In another embodiment, the invention features fragments of the proteins having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8, wherein the fragment comprises at least 15 amino acids (e.g., contiguous amino acids) of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8, respectively. In another embodiment, the protein, preferably a CSAPTP protein, has the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5, or SEQ ID NO:8.
Another embodiment of the invention features an isolated protein, preferably a CSAPTP protein, which is encoded by a nucleic acid molecule having a nucleotide sequence at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more homologous to a nucleotide sequence (e.g., to the entire length of the nucleotide sequence) including SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:9, respectively, or a complement thereof. This invention further features an isolated protein, preferably a CSAPTP protein, which is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:9, or a complement thereof.
The proteins of the present invention or biologically active portions thereof, can be operatively linked to a non-CSAPTP polypeptide (e.g., heterologous amino acid sequences) to form fusion proteins. The invention further features antibodies, such as monoclonal or polyclonal antibodies, that specifically bind proteins of the invention, preferably CSAPTP proteins. In addition, the CSAPTP proteins or biologically active portions thereof can be incorporated into pharmaceutical compositions, which optionally include pharmaceutically acceptable carriers.
In another aspect, the present invention provides a method for detecting the presence of a CSAPTP nucleic acid molecule, protein or polypeptide in a biological sample by contacting the biological sample with an agent capable of detecting a CSAPTP nucleic acid molecule, protein or polypeptide such that the presence of a CSAPTP nucleic acid molecule, protein or polypeptide is detected in the biological sample.
In another aspect, the present invention provides a method for detecting the presence of CSAPTP activity in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of CSAPTP activity such that the presence of CSAPTP activity is detected in the biological sample.
In another aspect, the invention provides a method for modulating CSAPTP activity comprising contacting a cell capable of expressing CSAPTP with an agent that modulates CSAPTP activity such that CSAPTP activity in the cell is modulated. In one embodiment, the agent inhibits CSAPTP activity. In another embodiment, the agent stimulates CSAPTP activity. In one embodiment, the agent is an antibody that specifically binds to a CSAPTP protein. In another embodiment, the agent modulates expression of CSAPTP by modulating transcription of a CSAPTP gene or translation of a CSAPTP mRNA. In yet another embodiment, the agent is a nucleic acid molecule having a nucleotide sequence that is antisense to the coding strand of a CSAPTP mRNA or a CSAPTP gene.
In one embodiment, the methods of the present invention are used to treat a subject having a disorder characterized by aberrant CSAPTP protein or nucleic acid expression or activity by administering an agent which is a CSAPTP modulator to the subject. In one embodiment, the CSAPTP modulator is a CSAPTP protein. In another embodiment the CSAPTP modulator is a CSAPTP nucleic acid molecule. In yet another embodiment, the CSAPTP modulator is a peptide, peptidomimetic, or other small molecule. In a preferred embodiment, the disorder characterized by aberrant CSAPTP protein or nucleic acid expression is an immune disorder, an anti-proliferative disorder, a proliferative disorder, e.g., cancer, for example sporadic cancers e.g., brain, breast and prostate; inherited autosomal-dominant cancer, e.g., Cowden""s syndrome; renal and lung carcinomas; metabolic disorder, e.g., diabetes, for example, impaired dephosphorylation of both the insulin receptor and insulin receptor substrate 1; viral pathogenesis, e.g., cancer, for example, adenovirus E1A-mediated cell proliferation; e.g., Boubonic Plague, for example, pathogenic Yersinia pestis viral PTPase dephosphorylation of host phospho-proteins; a neural disorder, a cardiovascular disorder, e.g., congestive heart failure, or a disorder arising from improper dephosphorylation of phosphorylated protein.
The present invention also provides a diagnostic assay for identifying the presence or absence of a genetic alteration characterized by at least one of (i) aberrant modification or mutation of a gene encoding a CSAPTP protein; (ii) mis-regulation of the gene; and (iii) aberrant post-translational modification of a CSAPTP protein, wherein a wild-type form of the gene encodes a protein with a CSAPTP activity.
In another aspect the invention provides a method for identifying a compound that binds to or modulates the activity of a CSAPTP protein, by providing an indicator composition comprising a CSAPTP protein having CSAPTP activity, contacting the indicator composition with a test compound, and determining the effect of the test compound on CSAPTP activity in the indicator composition to identify a compound that modulates the activity of a CSAPTP protein.
Other features and advantages of the invention will be apparent from the following detailed description and claims.